The mechanism of inhibition of ribonucleic acid synthesis by 8-hydroxyquinoline and the antibiotic lomofungin.

Abstract

RNA synthesis in yeast is rapidly inhibited by 8-hydroxyquinoline and the phenazine antibiotic lomofungin (5-formyl-1-methoxycarbonyl-4,6,8-trihydroxyphenazine). It is shown that lomofungin, like 8-hydroxyquinoline, is a chelating agent for bivalent cations. The mechanism of inhibition of RNA synthesis by lomofungin and 8-hydroxyquinoline was investigated in experiments with isolated Escherichia coli RNA polymerase. The results show that both inhibitors are capable of inhibiting polymerase activity solely by chelating the dissociable cations Mn2+ and Mg2+. Evidence is presented which shows that inhibition may occur in the absence of any direct contact between the RNA polymerase or DNA template and the inhibitor. The possibility that inhibition might also occur by chelation of the Zn2+, which is tightly bound to the polymerase, is discussed: it is concluded that lomofungin or 8-hydroxyquinoline is likely to inhibit the enzyme by removal of Mn2+ and Mg2+ before chelating the Zn2+. On the basis of inhibition by chelation of Mn2+ and Mg2+, explanations are proposed for why lomofungin and 8-hydroxyquinoline inhibit synthesis of ribosomal and polydisperse RNA more than that of 5S RNA and tRNA, and for why protein synthesis is not immediately inhibited in the intact yeast cell.

Indole-3-acetic acid in plant–pathogen interactions: a key molecule for in planta bacterial virulence and fitness

“…This quinoline derivative is produced by plants in nature, generally secreted into their exudates and used as an antimicrobial agent in agriculture and other industrial sectors during chemical synthesis. Several mechanisms have been proposed to support 8-HQ antibiotic-like activity, such as a lipophilic chelator and an inhibitor of TTSS, of multi-drug efflux pumps and of ribonucleic acid synthesis, although definitive evidence is not yet available [66,67]. Overall, PM data concerning the sensitivity of both DiaaL and DiaaM to 8-HQ was also confirmed for P. savastanoi pv.…”

Roles of divalent cations and pH in mechanism of action of nitroxoline against Escherichia coli strains

“…However, it is interesting to observe that an analog of NIT, 8-hydroxyquinoline, inhibits the RNA polymerase in yeasts solely by chelating the Mg 2ϩ and Mn 2ϩ cations required for enzyme activity (18,19). The same investigators reported that oxine is also capable of inhibiting isolated E. coli RNA polymerase by essentially removing Mn 2ϩ and Mg 2ϩ in the absence of any direct contact between oxine and the enzyme (19). In our study, the magnesium ions, in contrast to manganese, were found to play a major role in the reduction of NIT activity.…”

An Investigation into the Potential Use of Chelating Agents and Antibiotics as Synchrony Inducers in the Fission Yeast Schizosaccharomyces pombe

“…The effects of the antibiotic chelating agent lomofungin are similar to those of HQ (Fraser & Creanor, 1975), where the inhibition of DNA-dependent RNA polymerase Synchronization of cell division by chelators 399 activity by these agents almost certainly occurs through the ability to chelate Mg2+ and Mn2+. Complete inhibition of cell division in S. pombe by the highest concentration of the antibiotic employed (5 pg ml-l) took about 1.5 h (Fig.…”

“…In molecular terms, lomofungin is an effective chelator of both Mgz+ and Mn2+ (Fraser & Creanor, 1975). Figure 7 ( a ) shows that the minimum inhibitory concentration of lomofungin for a growing culture of S. pombe was 2.5 pg ml-l. At 1 pg ml-l, the antibiotic produced only a partial inhibition of cell division from which the cells recovered after a prolonged growth period of 24 h. The effect of exposing a growing culture of S. pombe to a 1 h pulse of lomofungin at 2.5 pg ml-l is shown in Fig.…”